James C. Cleland

Non-dystrophic myotonia: prospective study of objective and patient reported outcomes

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Few prospective studies have evaluated the sensitivity of symptoms and signs of myotonia in a large cohort of patients. We performed a prospective observational study of 95 participants with definite or clinically suspected non-dystrophic myotonia recruited from six sites in the USA, UK and Canada between March 2006 and March 2009. We used the common infrastructure and data elements provided by the NIH-funded Rare Disease Clinical Research Network. Outcomes included a standardized symptom interview and physical exam; the Short Form-36 and the Individualized Neuromuscular Quality of Life instruments; electrophysiological short and prolonged exercise tests; manual muscle testing; and a modified get-up-and-go test. Thirty-two participants had chloride channel mutations, 34 had sodium channel mutations, nine had myotonic dystrophy type 2, one had myotonic dystrophy type 1, and 17 had no identified mutation. Phenotype comparisons were restricted to those with sodium channel mutations, chloride channel mutations, and myotonic dystrophy type 2. Muscle stiffness was the most prominent symptom overall, seen in 66.7% to 100% of participants. In comparison with chloride channel mutations, participants with sodium mutations had an earlier age of onset of stiffness (5 years versus 10 years), frequent eye closure myotonia (73.5% versus 25%), more impairment on the Individualized Neuromuscular Quality of Life summary score (20.0 versus 9.44), and paradoxical eye closure myotonia (50% versus 0%). Handgrip myotonia was seen in three-quarters of participants, with warm up of myotonia in 75% chloride channel mutations, but also 35.3% of sodium channel mutations. The short exercise test showed ≥10% decrement in the compound muscle action potential amplitude in 59.3% of chloride channel participants compared with 27.6% of sodium channel participants, which increased post-cooling to 57.6% in sodium channel mutations. In evaluation of patients with clinical and electrical myotonia, despite considerable phenotypic overlap, the presence of eye closure myotonia, paradoxical myotonia, and an increase in short exercise test sensitivity post-cooling suggest sodium channel mutations. Outcomes designed to measure stiffness or the electrophysiological correlates of stiffness may prove useful for future clinical trials, regardless of underlying mutation, and include patient-reported stiffness, bedside manoeuvres to evaluate myotonia, muscle specific quality of life instruments and short exercise testing.

Treatment of neuromuscular channelopathies: Current concepts and future prospects

SummaryOur understanding of the molecular pathogenesis of the neuromuscular ion channelopathies has increased rapidly over the past two decades due to the identification of many of the genes whose mutation causes these diseases. These molecular discoveries have facilitated identification and classification of the hereditary periodic paralyses and the myotonias, and are likely to shed light on acquired ion channelopathies as well. Despite our better understanding of the pathogenesis of these disorders, current treatments are largely empirical and the evidence in favor of specific therapy largely anecdotal. For periodic paralysis, dichlorphenamide—a carbonic anhydrase inhibitor — has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and hypokalemic periodic paralysis. A second trial, comparing dichlorphenamide with acetazolamide versus placebo, is currently in progress. For myotonia, there is only anecdotal evidence for treatment, but a controlled trial of mexiletine versus placebo is currently being funded by a Food and Drug Administration—orphan products grant and is scheduled to begin in late 2008. In the future, mechanism-based approaches are likely to be developed. For example, exciting advances have already been made in one disorder, myotonic dystrophy-1 (DM-1). In a mouse model of DM-1, a morpholino antisense oligonucleuotide targeting the 3′ splice site of CLCN1 exon 7a repaired the RNA splicing defect by promoting the production of full-length chloride channel transcripts. Abnormal chloride conductance was restored, and myotonia was abolished. Similar strategies hold potential for DM-2. The era of molecularly-based treatments is about to begin.

Dispersion of compound muscle action potential in hereditary neuropathies and chronic inflammatory demyelinating polyneuropathy

Distal compound muscle action potential (DCMAP) dispersion, defined as a DCMAP duration ≥9 ms, and proximal‐distal (P‐D) CMAP dispersion are considered useful in the electrodiagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Distal and P‐D CMAP dispersion have not been fully studied in hereditary neuropathies, and it is not known whether these measures distinguish hereditary from acquired demyelination. We compared DCMAP duration and P‐D CMAP dispersion in 91 genetically characterized hereditary neuropathies and 33 subjects with CIDP. DCMAP dispersion was more frequent in nerves affected by CIDP (41.5%) than in Charcot–Marie–Tooth disease (CMT)1A (24.4%), CMT1B (7.4%), hereditary neuropathy with liability to pressure palsies (HNPP) (10.5%), or CMTX (9.8%). P‐D CMAP dispersion was more frequent in CIDP (27.7% of nerves) than in hereditary neuropathies (16.3%) when applying American Academy of Neurology (AAN) criteria; however, its frequency was similar in CIDP and the hereditary neuropathies using the more restrictive criteria of the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). Although dispersion is more common in CIDP than in the hereditary neuropathies, DCMAP and P‐D dispersion occur in at least one motor nerve in a significant proportion of hereditary neuropathies, and cannot be used in isolation to distinguish acquired from hereditary demyelination. Muscle Nerve, 2006

Acute inflammatory demyelinating polyneuropathy: contribution of a dispersed distal compound muscle action potential to electrodiagnosis.

Prolonged duration of the distal compound muscle action potential (DCMAP) (“DCMAP dispersion”) is useful in the electrodiagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) with good specificity in distinguishing CIDP from amyotrophic lateral sclerosis (ALS) and diabetic polyneuropathy, but its role in the electrodiagnosis of acute inflammatory demyelinating polyneuropathy (AIDP) is unclear. This study addresses this issue by determining the optimal cutoff for DCMAP duration using receiver operating characteristic (ROC) analysis in 207 motor nerves from 53 clinically defined AIDP patients compared to 148 motor nerves from 55 ALS patients. We also determined whether the presence of DCMAP dispersion improves the sensitivity of four of the most sensitive published sets of electrodiagnostic criteria for AIDP. Using the ROC‐derived optimal DCMAP duration cutoff of 8.5 ms, DCMAP dispersion was found in at least one motor nerve in 66% of subjects with AIDP compared to 9% of subjects with ALS. DCMAP dispersion improved the sensitivity of the four tested criteria sets to 76%–87% from 43%–77%. Moreover, of 13 AIDP patients who met none of the four published criteria sets, 5 (38%) had at least one dispersed DCMAP. These findings indicate that the presence of DCMAP dispersion adds electrodiagnostic sensitivity to the currently published criteria sets, while maintaining reasonably high specificity against a prototypical disorder of the primary motor neuron with axon loss. Muscle Nerve, 2006

Dispersion of the distal compound muscle action potential in chronic inflammatory demyelinating polyneuropathy and carpal tunnel syndrome.

Median neuropathy at the wrist can confound the electrodiagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP), since both conditions can prolong median distal motor latency. Dispersion of the distal CMAP (DCMAP) has recently emerged as a potentially useful adjunct in the electrodiagnosis of CIDP, with good specificity in distinguishing CIDP from certain axon‐loss disorders. However, it is uncertain whether focal compression neuropathies produce dispersion of the DCMAP in a manner similar to CIDP. In this study we compared median DCMAP duration in 27 patients with CIDP and 86 with carpal tunnel syndrome, using 39 patients with non‐neuropathic musculoskeletal pain syndromes as electrophysiologic controls. We found that, in contrast to CIDP, dispersion of the median DCMAP is uncommon, even in advanced carpal tunnel syndrome, being seen in only 8 of 103 (7.8%) hands. Although the pathophysiologic reasons for a differential effect of focal compression‐mediated demyelination and multifocal immune‐mediated demyelination (CIDP) on DCMAP duration are uncertain, our findings suggest that the presence of dispersion of the median DCMAP may prove useful in distinguishing immune‐mediated demyelination from compression neuropathy alone. Muscle Nerve 28: 189–193, 2003

Autonomic dysfunction is a major feature of cerebellar ataxia, neuropathy, vestibular areflexia ‘CANVAS’ syndrome

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative ganglionopathy. Prompted by the presence of symptomatic postural hypotension in two patients with CANVAS, we hypothesized that autonomic dysfunction may be an associated feature of the syndrome. We assessed symptoms of autonomic dysfunction and performed autonomic nervous system testing among 26 patients from New Zealand. After excluding three patients with diabetes mellitus, 83% had evidence of autonomic dysfunction; all patients had at least one autonomic symptom and 91% had more than two symptoms. We also found a higher rate of downbeat nystagmus (65%) than previously described in CANVAS. We confirmed that sensory findings on nerve conduction tests were consistent with a sensory ganglionopathy and describe two patients with loss of trigeminal sensation consistent with previous pathological descriptions of trigeminal sensory ganglionopathy. Our results suggest that autonomic dysfunction is a major feature of CANVAS. This has implications for the management of patients with CANVAS as the autonomic symptoms may be amenable to treatment. The findings also provide an important differential diagnosis from multiple system atrophy for patients who present with ataxia and autonomic failure.

Clinical evaluation of membrane excitability in muscle channel disorders: potential applications in clinical trials.

SummaryMuscle channelopathies are inherited disorders that cause paralysis and myotonia. Molecular technology has contributed immeasurably to diagnostic testing, to correlation of genotype with phenotype, and to insight into the pathophysiology of these disorders. In most cases, the diagnosis of muscle channelopathy is still made on clinical grounds, but is supported by ancillary laboratory and electrodiagnostic testing such as serum potassium measurement, exercise testing, repetitive nerve stimulation, needle electromyography, calculation of muscle fiber conduction velocity, or electromyography power spectra. Although provocative glucose or potassium challenges are now infrequently performed, they have contributed greatly to our understanding of the pathophysiology of these disorders, and to our ability to differentiate between periodic paralysis types. Despite considerable progress, ample opportunity remains for future clinical research, particularly in expanding genotype—phenotype correlations and in optimizing electrodiagnostic methods. With respect to diagnostic testing, there is a need for accurate, efficient, and cost-effective bedside testing, given the substantial proportion (as high as 20%) of genetically undefined cases. Even in genetically defined cases, minimal clinical expressivity due to incomplete penetrance poses a significant challenge to currently available nonmolecular testing.

Andersen‐Tawil syndrome presenting as a fixed myopathy

Andersen-Tawil syndrome (ATS) is a rare cause of periodic paralysis. It is characterized by periodic paralysis, cardiac dysrhythmias, and distinct physical characteristics. We report a patient in whom the diagnosis was made in the fifth decade after he presented with a fixed myopathy, and in whom electrodiagnostic testing after treatment mirrored the patient’s report of improved muscle strength despite an absence of objective clinical strengthening. A 43-year-old man presented with progressive proximal muscle weakness. A diagnosis of Becker muscular dystrophy (BMD) had been made in childhood based on calf hypertrophy, myopathic abnormalities on muscle biopsy (right deltoid, before availability of dystrophin staining), and mildly elevated creatine kinase (330 U/ L). He was referred when his son presented with similar symptoms, suggesting an autosomal dominant condition rather than x-linked Becker dystrophy. The patient reported slowly worsening gait and difficulty getting out of chairs and walking up stairs. He also described day-today fluctuations in muscle strength but did not describe well-defined spontaneous attacks of weakness. On examination, there was wasting of the sternocleidomastoid and upper pectoral muscles, moderate proximal upper and lower limb weakness (Medical Research Council [MRC] Grade 4 to 41), and normal distal power. There was mild retrognathia, low-set ears, and tapered fingers with clinodactyly. His electrocardiogram (ECG) showed a prolonged QTc of 484 ms. A needle electromyography (EMG) study showed subtle myopathic changes without myotonia (right deltoid, biceps, and first dorsal interosseous). Sensory nerve conduction studies were normal. Motor nerve studies showed normal conduction velocities but a low right ulnar compound muscle action potential (CMAP) amplitude of 3.0 mV (abductor digiti minimi, normal 6.0 mV) that normalized with exercise (7 mV, 130% increase) but was followed by a postexercise decrement of 86% (McManis long-exercise protocol). Genetic testing confirmed a c652C>T mutation in exon 2 of KCNJ2. Within days of starting acetazolamide 250 mg twice daily and oral potassium supplements, he reported improvement in baseline muscle strength (e.g., being able to lift his arms above his head), and later, on a dose of 500 mg twice daily, a reduction in the frequency and severity of the variable weakness. Clinical examination confirmed unchanged proximal weakness. A McManis test after 15 days of treatment showed an improved baseline right ulnar CMAP amplitude of 4.4 mV but an attenuated exercise-related increment (45% vs. 130%) and attenuated postexercise decrement (53% vs. 86%) vs. pretreatment. Although described in other muscle channelopathies, the unusual feature of this case is the presentation in adulthood of a chronic progressive myopathy, rather than discrete paralytic attacks, and the potential partial reversibility of the weakness with treatment. In addition, the value of repeated exercise CMAP testing is illustrated by the reduction in CMAP decrement postexercise, as well as the improvement in baseline CMAP amplitude both of which mirror the patient’s report of improvement in strength, despite no change in MRC grade. Although it is unclear whether early treatment prevents the late but progressive myopathy associated with ATS, the partial reversibility of the periodic weakness and the risk of cardiac death associated with ATS both argue in favor of early diagnosis.

Hypoventilation in glycine-receptor antibody related progressive encephalomyelitis, rigidity and myoclonus

Glycine receptor (GlyR) antibodies have been identified in patients with rigidity and hyperekplexia, but the clinical phenotype associated with these antibodies has not been fully elucidated. The clinical features in two additional patients with GlyR antibodies are described. A 55-year-old man presented with stimulus-induced hyperekplexia and rigidity in the lower limbs and trunk. He initially responded to benzodiazepines, but presented after 18 months with severe, painful, prolonged spasms associated with supraventricular and ventricular arrhythmias, hypoventilation and oxygen desaturation requiring intubation. He improved following treatment with clonazepam, baclofen and immunomodulatory therapies. A 58-year-old woman presented with stiffness in the legs and hyperekplexia associated with hypoventilation, at times leading to loss of consciousness. She responded to benzodiazepines and has remained in remission. The clinical picture associated with GlyR antibodies includes autonomic dysfunction, cardiac arrhythmias and hypoventilation. It is important to recognise these serious complications early to limit mortality from this treatable condition.

31 – Channelopathies of the Nervous System

Few neurological disorders can claim as long a passage of time between initial description and subsequent molecular characterization as the channelopathies, which are acquired or inherited disorders of membrane ion channel function. Mutations have now been identified for most channelopathies, and ongoing research suggests that these disorders are relatively common. This chapter focuses on the inherited disorders of ion channel function. However, acquired ion channel disorders due to autoimmune, paraneoplastic, and toxic causes are well described and the pathophysiology is well characterized. Ion channels facilitate rapid communication of electrical information in the central, peripheral, and autonomic nervous systems. So fundamental is the function that interference by channel-blocking toxins can have rapidly lethal effects. With the development of molecular techniques, channel structure is further elucidated through electrophysiological studies after cloning and expression in animal systems. Based on DNA sequence homology, channels initially thought to be electrophysiologically and pharmacologically distinct are now recognized as members of the same super family and may have evolved from a common ancestor.